Depakene Drug Interactions

Effects of Co-Administered Drugs on Valproate Clearance: Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.
Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme-inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported.
Drugs For Which a Potentially Important Interaction Has Been Observed: Aspirin: A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and in inhibition if metabolism of valproate. Valproate free fraction was increased four-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered.
Carbapenem Antibiotics: A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (ertapenem, imipenem, meropenem) and may result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates.
Cholestyramine: Cholestyramine may lead to a decrease in plasma level of valproate when co-administered.
Estrogen-Containing Hormonal Contraceptives: Estrogen-containing hormonal contraceptives may increase the clearance of valproate, which may result in decreased concentration of valproate and potentially increased seizure frequency. Prescribers should monitor serum valproate concentrations and clinical response when adding or discontinuing estrogen containing products, preferably during on-off intervals of the hormonal contraceptive cycle.
Felbamate: A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentrations by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentrations to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated.
Metamizole: Metamizole may decrease valproate serum levels when co-administered, which may result in potentially decreased valproate clinical efficacy. Prescribers should monitor clinical response (seizure control or mood control) and consider monitoring valproate serum levels as appropriate.
Methotrexate: Some case reports describe a significant decrease in valproate serum levels after methotrexate administration, with occurrence of seizures. Prescribers should monitor clinical response (seizure control or mood control) and consider monitoring valproate serum levels as appropriate.
Protease inhibitors: Protease inhibitors such as lopinavir, ritonavir decrease valproate plasma level when co-administered.
Rifampin: A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after five nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin.
Drugs For Which Either No Interaction or a Likely Clinically Unimportant Interaction Has Been Observed: Antacids: A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac-160 mEq doses) did not reveal any effect on the extent of absorption of valproate.
Chlorpromazine: A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg b.i.d.) revealed a 15% increase in trough plasma levels of valproate.
Haloperidol: A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg b.i.d.) revealed no significant changes in valproate trough plasma levels.
Cimetidine and Ranitidine: Cimetidine and ranitidine do not affect the clearance of valproate.
Effects of Valproate on Other Drugs: Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronyltransferases.
The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported.
Drugs For Which a Potentially Important Valproate Interaction Has Been Observed: Amitriptyline/Nortriptyline: Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (ten males and five females) who received valproate (500 mg b.i.d.) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.
Carbamazepine/carbamazepine-10,11-Epoxide: Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.
Clonazepam: The concomitant use of valproic acid and clonazepam may induce absence status in patients with a history of absence type seizures.
Diazepam: Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate.
Ethosuximide: Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.
Lamotrigine: In a steady-state study involving ten healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration.
Phenobarbital: Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg b.i.d. for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate.
There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate.
Phenytoin: Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg t.i.d.) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate.
In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.
Valproic acid metabolites levels may be increased in case of concomitant use with phenytoin or phenobarbital. Therefore patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonemia.
Pivalate-conjugated medicines: Concomitant administration of valproate and pivalate-conjugated medicines that decrease carnitine levels (such as cefditoren pivoxil, adefovir dipivoxil, pivmecillinam and pivampicillin) may trigger occurrence of hypocarnitinemia (see Patients at risk of hypocarnitinemia under Precautions). Concomitant administration of these medicines with valproate is not recommended. Patients in whom co-administration cannot be avoided should be carefully monitored for signs and symptoms of hypocarnitinemia.
Primidone: Primidone is metabolized into a barbiturate and therefore, may also be involved in a similar interaction with valproate as phenobarbital.
Propofol: A clinically significant interaction between valproate and propofol may occur leading to an increased blood level of propofol. Therefore, when co-administered with valproate, the dose of propofol should be reduced.
Nimodipine: Concomitant treatment of nimodipine with valproic acid may increase nimodipine plasma concentration by 50%.
Tolbutamide: From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown.
Cannabidiol: In patients of all ages receiving concomitantly cannabidiol at doses 10 to 25 mg/kg and valproate, clinical trials have reported ALT increases greater than 3 times the upper limit of normal in 19% of patients.
Drug Interaction between valproate and cannabidiol may result in an increased risk of elevation of liver transaminases (see Precautions).
Appropriate liver monitoring should be exercised when valproate is used with cannabidiol, and dose reductions or discontinuation should be considered in case of significant anomalies of liver parameters.
Topiramate and acetazolamide: Concomitant administration of valproate and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonemia.
Patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonemic encephalopathy.
Concomitant administration of topiramate with valproic acid has also been associated with hypothermia in patients who have tolerated either drug alone. Blood ammonia levels should be measured in patients with reported onset of hypothermia (see Precautions).
Warfarin: In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if divalproex sodium therapy is instituted in patients taking anticoagulants.
Zidovudine: In six patients, who were seropositive for HIV, the clearance of zidovudine (100 mg every eight hours) was decreased by 38% after administration of valproate (250 or 500 mg every eight hours); the half-life of zidovudine was unaffected.
Quetiapine: Co-administration of valproate and quetiapine may increase the risk of neutropenia/leucopenia.
Drugs For Which Either No Interaction or a Likely Clinically Unimportant Interaction Has Been Observed: Acetaminophen: Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients.
Clozapine: In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine.
Lithium: Co-administration of valproate (500 mg b.i.d.) and lithium carbonate (300 mg t.i.d.) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium.
Lorazepam: Concomitant administration of valproate (500 mg b.i.d.) and lorazepam (1 mg b.i.d.) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.
Olanzapine: Valproic acid may decrease the olanzapine plasma concentration.
Rufinamide: Valproic acid may lead to an increase in plasma level of rufinamide. This increase is dependent on concentration of valproic acid. Caution should be exercised, in particular in children, as this effect is larger in this population.